While the skin has long been considered the preferred route of administration for cosmetic applications and dermatological therapies, the introduction of transdermal nitroglycerin patches initiated use of the skin as a route for administering systemic drug therapy. Three types of known product applications which employ the barrier properties of the skin for drug delivery include cosmetic, tropical, and transdermal applications. The optimal delivery strategy for administering pharmaceuticals via the skin varies among individual pharmaceuticals and among different disease states.
Cosmetic applications are limited to negligible drug penetration past the stratum corneum. Thus, any carrier that minimizes penetration or that aids excipient retention within or onto the stratum corneum would be of tremendous advantage. For transdermal applications, steady state drug delivery is preferred. Steady state delivery requires the use of rate-controlling membranes that slow systemic breakthrough of highly permeable drugs such as nitroglycerin. This type of control can be achieved by using matrix type patches that modify delivery rates by using polymer adhesives and solvents. For topical delivery, minimal systemic breakthrough is always preferred. In order to adequately dose the viable epidermis and dermis, however, large amounts of drug must cross the intact skin barrier, i.e. the stratum corneum, or the lesional delivery barrier, i.e. scab, plaque, etc.
Some dermatological conditions, such as acne, require multiple delivery strategies because they have multiple delivery requirements. Acne is chronic pilosebaceous unit inflammation associated with the face and trunk usually occurring in adolescence due to complex interactions of androgens and bacteria. For the adolescent, circulating androgen results in significantly increased sebum production. The sebaceous glands dramatically enlarge and excrete more sebum than the immature pilosebaceous canals can accommodate. Simultaneously, anaerobic bacteria (Propionibacterium acnes) that feed upon the sebum, converting triglycerides to fatty acids, dramatically increase in number due to an increase in volume of the nutrition source. The increase in constricted immature ducts and bacterial waste products results in plugged follicles and typical acne inflammation. Acne severity for a particular anatomical location parallels the number of sebaceous glands per unit of skin.
Acne, which is often treated with antibiotics, is one condition where a highly specialized topical drug delivery is needed. Ideally, a topical antimicrobial would be primarily delivered into the pilosebaceous unit, with only minimal active crossing of the skin barrier. Intact stratum corneum lines the upper third of the pilosebaceous unit, and it is into this upper third of the hair follicle that the sebaceous duct secretes sebum. Thus, a need exists for an acne treatment that maximizes antimicrobial drug levels in the upper third of the pilosebaceous unit.
Additionally, when an anti-inflammatory agent is used to treat acne, it is important to increase the level of drug that will cross the intact stratum corneum lining the upper third of the pilosebaceous unit. By definition, inflammation is the response of the viable epidermis to irritants and sensitizers. In order to reduce the amount of inflammation, the active pharmaceutical must penetrate past the stratum corneum and interfere with the cascade of inflammatory events. Ideally, delivery of an anti-inflammatory for acne requires that steady-state levels be sustained. To date, the ideal delivery system that provides antimicrobial agents above the stratum corneum while providing anti-inflammatory agents below the stratum corneum has not been implemented.
Other dermatological conditions, such as herpes lesions, require multiple delivery strategies because the barrier properties of the lesion dramatically change in the course of the disease. Starting with the prodrome and progressing through the formation of vesicles, the lesion has an intact stratum corneum delivery barrier, and thus, maximum penetration of the drug is necessary. While in place, the stratum corneum delays penetration to the target tissue and sustains the time that the dissolved active drug resides in the target tissue. During this stage of the lesion, microparticulate drug will not significantly cross the intact stratum corneum, and thus, has no real effect in treatment of the lesion. Once the herpes lesion vesicles rupture, the stratum corneum is no longer in place, and the dissolved drug rapidly sweeps past the target tissue, providing minimal or insignificant benefit. However, from the time that the vesicle ruptures and through to the complete formation of the scab, the microparticulate drug is deposited directly at the target area, where it can slowly be released for sustained and significant therapeutic benefit. Thus, in order to adequately dose the viable epidermis from the prodrome through the time of scab formation in a herpes lesion, two distinctly different drug delivery strategies must be implemented.
While the dermatological conditions of acne and herpes lesions serve as conceptual examples of how therapeutic approaches can require dramatically different drug delivery profiles, all skin diseases are best treated by a particular drug delivery strategy tailored specifically to the pharmaceutical and the particular disease. Some diseases are best treated using pulsed or spiked delivery in which high levels of drug are delivered in a short period of time. This type of treatment saturates receptor sites and provides maximum microbial or viral replication inhibition, thus providing optimal therapy for certain diseases. Conversely, a cosmetic, topical, or transdermal product that provides steady state active pharmaceutical delivery while minimizing excipient delivery provides the preferred skin delivery profile for other diseases. Thus, a carrier system that can be adjusted to optimize the delivery profile for the pharmacology of the active drug and the nature of the disease state is needed to advance the effectiveness of pharmaceutical products applied to the skin.